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Interrelations between translation and general mRNA degradation in yeast

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Messenger RNA (mRNA) degradation is an important element of gene expression that can be modulated by alterations in translation, such as reductions in initiation or elongation rates. Reducing translation initiation strongly affects mRNA degradation by driving mRNA toward the assembly of a decapping complex, leading to decapping. While mRNA stability decreases as a consequence of translational inhibition, in apparent contradiction several external stresses both inhibit translation initiation and stabilize mRNA. A key difference in these processes is that stresses induce multiple responses, one of which stabilizes mRNAs at the initial and rate‐limiting step of general mRNA decay. Because this increase in mRNA stability is directly induced by stress, it is independent of the translational effects of stress, which provide the cell with an opportunity to assess its response to changing environmental conditions. After assessment, the cell can store mRNAs, reinitiate their translation or, alternatively, embark on a program of enhanced mRNA decay en masse. Finally, recent results suggest that mRNA decay is not limited to non‐translating messages and can occur when ribosomes are not initiating but are still elongating on mRNA. This review will discuss the models for the mechanisms of these processes and recent developments in understanding the relationship between translation and general mRNA degradation, with a focus on yeast as a model system. WIREs RNA 2014, 5:747–763. doi: 10.1002/wrna.1244 This article is categorized under: RNA Turnover and Surveillance > Regulation of RNA Stability
Mechanism of messenger RNA (mRNA) degradation. The degradation of mRNA begins on the newly cytoplasmic mRNA. The decay process is regulated by elements on each end of the mRNA. The mRNA has a 7‐methyl‐guanosine cap at the 5′ end and a poly(A) tail at the 3′ end. The poly(A) length is approximately 60 nucleotides upon export. In the cytoplasm, the mRNA is initially deadenylated by Pan2/3 and then primarily by the Ccr4/Pop2/Not deadenylase complex, resulting in a median poly(A) length of approximately 30 nucleotides. Once the poly(A) tail is shortened to a length that is no longer able to bind Pab1p, the mRNA can be degraded from the 3′→5′ direction by the exosome. The 5′→3′ degradation pathway requires the mRNA to be first decapped by the decapping complex Dcp1/2 and then degraded by the Xrn1p exonuclease enzyme.
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Detection of slowed elongation by Dhh1p. Slowed ribosomal elongation of a translating messenger RNA (mRNA) containing rare codons or other slow stretches of mRNA (indicated in pink) is detected by Dhh1p, resulting in accelerated decapping by the decapping complex Dcp1/2 and consequent degradation of the mRNA by the exonuclease Xrn1p.
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Dhh1p‐mediated inhibition of ribosomal translocation. A translating messenger RNA (mRNA) directly or indirectly recruits Dhh1p. Once associated with an mRNA, Dhh1p acts to inhibit elongation of the message by the ribosomes. The affected mRNA can then undergo one of three fate choices: 5′→3′ degradation by decapping and exonucleolytic decay, storage in P bodies, or other structures or accumulation of translationally slowed ribosomes.
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Co‐translational messenger RNA (mRNA) decay. A translating mRNA is decapped by the Dcp1/2 decapping complex. Once the 5′ 7‐methyl‐guanosine cap is removed by the decapping enzyme, 5′→3′ exonucleolytic decay mediated by the exonuclease Xrn1p proceeds. During decay, the ribosomes block the exonuclease until they translocate off the mRNA.
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Extrinsic inhibition of translation and messenger RNA (mRNA) stability. Stress external to the cell is sensed and initiates a host of responses, including the inhibition of translation initiation. The first step in the common mRNA decay pathway is deadenylation, which is inhibited by extrinsic effects on translation by an unknown mechanism. Once acclimated to the stress, the cell will either degrade mRNAs, re‐commence translation or place mRNAs into non‐translating storage.
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Intrinsic inhibition of translation and messenger RNA (mRNA) stability. Intrinsic inhibition of translation directly or indirectly inhibits initiation on specific messages. Subsequent to inhibition, mRNA is freed from ribosomes as they translocate off the mRNA. Decapping activators assemble on mRNA, predominantly at the 3′ UTR, and recruit the decapping enzyme. mRNA is decapped and degraded by Xrn1p in the 5′→3′ direction.
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Initiation of translation. Messenger RNA (mRNA) translation begins after export, with association with translation initiation factors including eIF4E, eIF4G, and Pab1p. Translation initiation begins with the formation of the 43S preinitiation complex consisting of the small ribosomal subunit (40S), methionyl tRNA, and additional initiation factors. The preinitiation complex binds to the mRNA to form a 48S complex. The small ribosomal subunit then scans the message in the 5′→3′ direction until it recognizes an AUG codon. In association with other initiation factors, the large ribosomal subunit (60S) forms an 80S complex, which commences translation.
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